Phase II Evaluation of Cannabidiol as an Adjunctive Therapy in Inpatient Alcohol Cessation for Severe Alcohol Use Disorder Patients

The primary objective of this Phase II trial is to evaluate the efficacy of **cannabidiol** as an add-on treatment in increasing the abstinence maintenance rate at week 6 of the study, which is one month after discharge from a scheduled inpatient alcohol withdrawal stay. This is clinically relevant as maintaining abstinence is a critical challenge in the management of patients with severe Alcohol Use Disorder, and improving this outcome could significantly enhance long-term recovery prospects.

Secondary objectives include:

• Assessing the safety of 10 days of up to 900 mg of cannabidiol as an add-on to usual care in patients with severe Alcohol Use Disorder during inpatient alcohol cessation.
• In case of relapse, reducing alcohol use after discharge up to week 6 of the study.
• Reducing alcohol withdrawal symptoms during inpatient alcohol cessation.
• Reducing anxiety symptoms during inpatient alcohol cessation.
• In a sub-group of patients, describing the CBD plasmatic rate and testing if it is correlated with side effects and/or efficacy.
• In the sub-group of patients with co-occurring cannabis use, reducing cannabis use after discharge up to week 6 of the study.

The clinical trial involves **patients with severe Alcohol Use Disorder** as defined by DSM 5 criteria, who are undergoing a scheduled inpatient alcohol cessation attempt. The study population includes both male and female participants, aged between 18 and 75 years. Participants are required to be in general good health aside from their alcohol use disorder and must have current social insurance. The trial does not focus on a vulnerable population. Participants were selected based on their hospitalization for a scheduled alcohol cessation, willingness to participate, and ability to provide informed consent. Females of childbearing age are required to use an effective contraceptive method during the treatment and for seven days following treatment administration. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the efficacy of **cannabidiol** as an add-on treatment during inpatient alcohol cessation in patients with severe **alcohol use disorder**. This is a Phase II, randomized, double-blind, placebo-controlled trial with three comparative groups. The primary objective is to increase the abstinence maintenance rate at week 6 of the study, which is one month after discharge from the scheduled alcohol withdrawal inpatient stay. The trial is expected to commence recruitment on July 3, 2024, and conclude by August 17, 2026.

Participants will be randomly assigned to receive either Arvisol 150mg, a placebo, or another comparator. The trial will involve oral administration of the investigational product, with a maximum daily dose of 900 mg and a total dose not exceeding 9900 mg over a treatment period of up to 11 days. The study will include several visits: an initial screening visit, daily assessments from Day 0 to Day 10, and four weekly follow-up visits after discharge, culminating in an end-of-study visit at week 6.

The inclusion criteria require participants to be hospitalized for a scheduled alcohol cessation, aged between 18 and 75 years, meeting DSM 5 criteria for severe alcohol use disorder, and willing to provide informed consent. Females of childbearing potential must use effective contraception during treatment and for seven days post-treatment. The primary endpoint is the percentage of patients with documented continuous abstinence at month 1 post-discharge, confirmed through self-reports and clinical examinations, including urinary assessments for ethyl glucuronide.

Secondary endpoints include monitoring side effects, relapse rates, alcohol withdrawal symptoms, anxiety levels, sleep quality, and substance use. In a subgroup of patients, plasma levels of **cannabidiol** will be measured. Participants are expected to be involved in the study for approximately six weeks. Conditions for early termination include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety.

The clinical trial involves the administration of **Arvisol 150mg**, an experimental medication containing the active substance **cannabidiol**. This medication is provided in the form of a **tablet** and is intended for **oral use**. The maximum daily dose is 900 mg, with a total maximum dose of 9900 mg over the course of the treatment period, which spans up to 11 weeks. The medication is manufactured by Echo Pharmaceuticals and is identified by the sponsor product code ECP015. The primary objective of the trial is to assess the efficacy of cannabidiol as an add-on treatment during inpatient alcohol cessation in patients with severe alcohol use disorder.

In addition to the experimental medication, the trial includes the use of **Arvisol placebo**. The placebo is designed to match the experimental medication in appearance and administration route, ensuring blinding of the study. The placebo is administered orally in a similar schedule to the active treatment, allowing for a controlled comparison of outcomes between the treatment and placebo groups. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

Efficacy in this clinical trial will be assessed primarily by evaluating the **abstinence maintenance rate** at week 6 of the study, which is one month after discharge from the scheduled alcohol withdrawal inpatient stay. The primary endpoint is the percentage of patients in each group who achieve documented continuous abstinence at this time point. Continuous abstinence will be determined through patient self-reports using standardized Time Line Follow Back (TLFB) scales, collected at the screening visit, daily from Day 0 to Day 10, and weekly after discharge up to week 6. This self-reported data will be corroborated by clinical examinations for signs of acute alcohol intoxication and six urinary assessments of ethyl glucuronide (Et-OH), conducted twice during the inpatient stay and weekly after discharge up to week 6.

Secondary endpoints include the documentation of possible side effects using the PRISE-M symptoms checklist, assessed daily from Day 1 to Day 10 and at each outpatient visit up to week 6. In cases of relapse, drinking days and drinks per day will be self-reported using TLFB scales. Additional assessments include alcohol withdrawal and craving scales (CIWA-R, LIKERT craving scale, and an adapted version of the OCDS), state anxiety scale (STAI-6), and the Pittsburgh Sleep Quality Index (PSQI). These will be measured at the screening visit, daily from Day 0 to Day 10, and weekly thereafter up to week 6. For a subgroup of patients, plasmatic levels of **cannabidiol (CBD)** will be measured on Day 5 and Day 10 using liquid chromatography coupled to high-resolution mass spectrometry (LCMSHR). Self-reported use of other substances will also be collected using TLFB scales, and for current cannabis users, urinary cannabinoid levels will be quantitatively determined using LCMSHR.