In order to appropriately test and validate this model for AUD, we will use an established, FDA-approved medication. NTX is an opioid antagonist with high affinity for mu-opioid and kappa-opioid receptors. Preclinical studies have shown that opioid antagonists at the muopioid receptor reduce ethanol consumption. In humans, alcohol consumption increases the release of endogenous opioids in the mesolimbic dopamine reward system which contributes to the subjective pleasurable effects of alcohol. Therefore, NTX’s therapeutic benefit as an opioid antagonist is proposed to block these rewarding effects and reduce alcohol consumption. Previous studies of NTX have shown that it reduces drinks per drinking day, alcohol craving, rates of relapse, and the subjective pleasurable effects of alcohol. The effects of NTX appear to be moderated by craving such that higher levels of craving were found to be associated with greater reduction in alcohol consumption. As an established medication for AUD, NTX is an ideal candidate to test the novel practice quit attempt model. To further validate this novel early efficacy model, we will also test a promising medication to treat AUD. Varenicline is a partial agonist at α4β2 and a full agonist at α7 nicotinic acetylcholine receptors, which is FDA-approved for smoking cessation. In preclinical studies, activation of nicotinic acetylcholine receptors reduced ethanol consumption. In human laboratory studies, VAR reduced alcohol self-administration and craving, compared to placebo. In smoking cessation trials, it also reduced alcohol consumption and craving.
Additionally, a multi-site randomized controlled trial of VAR in individuals with AUD found that it reduced drinks per drinking day, alcohol craving,cannabis grow supplies and percentage of heavy drinking days. Together, these studies suggest that VAR is a promising pharmacotherapy for the treatment of AUD. Therefore, including varenicline, a widely studied and promising AUD pharmacotherapy, as a third arm in this study will enable us to further validate this novel alcohol quit paradigm. In designing the current study as a 3-arm trial, we benefit not only from establishing the efficacy of NTX and VAR against placebo, but also from a head-to-head comparison of NTX and VAR in a cost-effective manner. The 3-arm trial design has been selected to overcome weaknesses present in non-inferiority trials where a novel drug is compared to an active control that is the current standard treatment. In active control trials, medication efficacy of the novel drug is determined by demonstrating non-inferiority to the active control, which rests on the critical assumption that the active control has an actual drug effect. However, as there is no placebo control, this assumption cannot be proven; therefore, non-inferiority/equivalence trials lack assay sensitivity, or the ability to distinguish between effective and ineffective treatments. The 3-arm design essentially combines the advantages of placebo and active controlled trials. The placebo arm will allow us to showcase if VAR is an effective or ineffective medication in the context of a good internal standard. Additionally, if neither NTX nor VAR are shown to be superior to placebo, then we can conclude that the practice quit paradigm is not a valid method for screening medications for AUD.The purpose of the current study is to develop and validate this novel model to screen novel compounds and advance medications development. Naltrexone was chosen to evaluate the novel practice quit attempt model as it is one of the few FDA-approved medications AUD.
RCT studies with oral NTX have shown that it reduced drinks per drinking day, alcohol craving, rates of relapse, and the subjective pleasurable effects of alcohol. As such, NTX represents a well-known, well-studied medication that is ideal for testing a novel paradigm. Varenicline is a promising pharmacotherapy for the treatment of AUD. VAR has been shown to reduce alcohol self-administration, consumption, and craving. A recent RCT of VAR in individuals with AUD found that it reduced drinks per drinking day, alcohol craving, and percentage of heavy drinking days. These studies suggest VAR as a potential AUD pharmacotherapy. The addition of VAR as a third arm in the current study will allow us to further validate this novel practice quit attempt model. Additionally, the inclusion of a promising pharmacotherapy allows us to compare the efficacy of two medications head to-head in a cost-effective manner. The 3-arm design of a novel medication , standard treatment , andplacebo allows us to not only establish efficacy of each medication against placebo, but also of the novel medication again the standard treatment. This study design essentially combines the advantages of placebo and active control studies.Participants who are eligible after the physical exam will be randomized to one of three treatment conditions . Urn randomization will be stratified by gender, smoking status , and drinking status . The UCLA Research Pharmacy will manage the blind. The three treatment conditions will not be different in appearance or method of administration. All participants will undergo a week long medication titration period prior to the onset of the practice quit attempt as follows: for the naltrexone condition, 12.5 mg will be taken for the first 3 days, followed by 25 mg dosage from days 4–7.
The target dosage of 50 mg will be ingested days 8–14. As for the varenicline condition, a dosage of 0.5 mg will be taken for the first 3 days followed by an increase to 1 mg for days 8–14. The intended dosage of 2 mg will be taken days 8–14. Each condition will the instructed to take prescribed medication twice per day as detailed in Table 1. On study day 1, participants will report to the laboratory to complete the alcohol CR paradigm and receive their first medication dose under direct observation of study staff. They will receive a 7-day supply of study medication in blister packs with AM and PM dosing clearly distinguished. After reaching the target medication dose at the end of 1 week, participants will come to the laboratory on study day 8 to receive their second, 7- day supply of study medication and to begin the 7-day practice quit attempt. Participants will be asked to take the AM dose of study medication on study day 8 in the lab under direct observation of study staff. During the practice quit attempt,cannabis grow facility participants will complete daily online and phone visits to report on their drinking, mood, and craving for alcohol during the previous day in a daily diary assessment . For each virtual visit, participants will be contacted over the phone by research staff. Participants will first be asked about adverse events and about use of concomitant medications. Research staff will then administer the CIWA-Ar to measure alcohol withdrawal. Next, they will ask participants to report on their past day drinking as well as cigarette and marijuana use. Finally, while participants are still on the phone, research staff will send a link to the DDA . All participants will meet with a trained study counselor briefly after the second cue exposure session on day 14. This brief intervention draws from motivational interviewing and Screening, Brief Intervention, and Referral to Treatment models. It uses the therapeutic stance of motivational interviewing which is collaborative and client-centered. Consistent with the literature on brief intervention, the therapist will seek opportunities to engage in and amplify change talk.
Together, the combination of evidence-based practices and principles applied to AUD, coupled with the experience of change in the context of study participation, is expected to result in an opportunity for health behavior change .Criteria for discontinuing or modifying allocated interventions are at the discretion of the study physicians or principal investigator. One week after beginning the medication, physicians will speak with the participant via phone call to check for any adverse events. If reported, participant may either undergo a dose-reduction or termination. Participants will also have the option to voluntarily discontinue all medication at any point. All severe adverse events will be reported to relevant reporting entities immediately.Adherence to interventions is facilitated by dividing the medication into separate blister packs for two distributions, the daily virtual visits during the practice quit attempt period, and a completion bonus. The separation of the study medication into two blister packs, each a 7-day supply, will motivate participants to come back to the laboratory for the second supply, and reduce the chance of them misplacing the medication at the start of the study. During the practice quit attempt period, the participants will be asked to send pictures of their blister packs to the study staff after completion of the daily phone visits. This will allow the study staff to count the medication for compliance. Additionally, a completion bonus will be given out to participants on the last day of the study if they have completed at 7 out of the 8 in-person and virtual visits. This is to motivate participants to complete all daily phone visits and online assessments .Participants will be recruited from the community through online and newspaper advertisements, as well as campaigns on multiple social media platforms .Targeted recruitment will also take place through a lab database of previous study participants who agreed to be contacted for future studies.Data are collected at the behavioral eligibility screening visit, the randomization visit , at each of the daily phone visits during the practice quit attempt period , and at the in-person study visits . All staff personnel will be trained on any relevant assessment procedures and inter-reliability will be monitored continuously by the primary investigator. For the drinking outcomes , data will be collected via participant self-report through the Timeline Follow back. The Alcohol Urge Questionnaire will be used in the CR paradigm to measure craving. The AUQ is an 8-item scale in which participants will rate their present experience of alcohol craving on a 7-point Likert scale. The AUQ has demonstrated high test-retest reliability, high internal consistency, and construct validity in human laboratory studies.Self-report measures will be directly completed through an electronic data capture electronic case report forms system, Qualtrics. Timeline Follow back data will be entered by research staff into excel in order to generate daily drink averages based on standard drink calculations. All other data will be entered by research staff onto SPSS. Data will be held on a secure server at the University of California, Los Angeles. Appropriately qualified personnel designated by the PI will monitor data entry and ensure that missing data are addressed as soon as possible after detection. All Timeline Follow back data will be double-checked by research staff to ensure validity. Excel will also be formulated to detect and notify in the case of any abnormal values.Participants will be given a 24-h telephone number to reach the study physician to discuss side effects, and physician office hours will be available as needed. Adverse events, including signs of sickness, will be collected in an open-ended format and coded using a systematic assessment for treatment emergent events format at each study visit . Vital signs will be monitored at the beginning of each in-person study visit. Alcohol withdrawal will be monitored at each visit through administration of the CIWA-Ar, and any significant withdrawal, as indicated by a score of 10 or more on the CIWA-Ar, will be reported to the study physician immediately. In the event that significant medical problems are encountered, the study blind will be broken and appropriate medical treatment will be provided.The PI will designate appropriately qualified personnel to periodically perform quality assurance checks at mutually convenient times during and after the study. These monitoring visits provide the opportunity to evaluate the progress of the study and to obtain information about potential problems. The monitor will assure that data are accurate and in agreement with any paper source documentation used, verify that subjects’ consent for study participation has been properly obtained and documented, confirm that research subjects entered into the study meet inclusion and exclusion criteria, verify that study procedures are being conducted according to the protocol guidelines, monitor review AEs and SAEs, and assure that all essential documentation required by GCP guidelines are appropriately filed. At the end of the study, they will confirm that the site has the appropriate essential documents on file and advise on storage of study records.Alcohol use disorder is a chronic condition with both high relapse and low treatment rates.