Cannabidiol as an add-on Treatment During Inpatient Alcohol Cessation in Patients With Severe Alcohol Use Disorder: a Phase ii Trial

Study Overview
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Brief Summary
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Randomized clinical trial of 10 days Cannabidiol versus placebo as an adjunctive treatment during inpatient alcohol detoxification to improve abstinence in patients with severe alcohol use disorder.

Detailed Description
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Secondary objectives : To assess the safety of 10 days of up to 900 mg of cannabidiol as an add-on to usual care in the specific population of 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 To reduce alcohol withdrawal symptoms during inpatient alcohol cessation To reduce anxiety symptoms during inpatient alcohol cessation In a sub-group of patients: describe CBD plasmatic rate and test if it is correlated with side-effects and/or efficacy In the sub-group of patients with co-occuring cannabis use, reducing cannabis use after discharge up to week 6 of the study Secondary endpoints : symptoms check list (PRISE-M) of possible side effects every day from day 1 to 10, and then at each outpatient study visit (4 (1 per week) after discharge up to week 6 of the study). Thus any side effect related to treatment exposure as well as treatment cessation (such as anxiety rebound or withdrawal symptoms related to CBD or increase in cannabis use) could be documented in case of relapse: drinking days and drinks per day (self-declared using standardized TLFB time line follow back scale over the past week) at the screening visit and daily from Day 0 to Day 10 and 4 (1 per week) after discharge up to week 6 of the study) alcohol withdrawal scales and craving scales (CIWA-R, , LIKERT craving scale and an adapt version of the OCDS) at the screening visit and every day from day 0 to 10 then at each study visit: 4 (1 per week) after discharge up to week 6 of the study state anxiety scale (STAI-6 the short form of the Spielberger inventory, composed of 6 Likert scales) at the screening visit and every day from day 0 to 10 then at each study visit: 4 (1 per week) after discharge up to week 6 of the study Pittsburgh Sleep Quality Index (PSQI) at the screening visit and the last visit. A modified daily version every day from day 0 to 10 then at each study visit a modified weekly version: 4 (1 per week) after discharge up to week 6 of the study in the subgroup of patients recruited in Fernand Widal hospital, plasmatic level of CBD will be determined twice: at D5 and D10 of the study by Dr Laurence Labat, head of the toxicology department of Lariboisière hospital. Analysis of cannabinoids in human biological specimens of plasma will rely on an extraction process and a chromatographic separation in LCMSHR (Liquid chromatography coupled to high resolution mass spectrometry) for quantification of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), 11-hydroxy Δ9-tetrahydrocannabinol (11-OH THC) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH) using deuterated molecules as internal standard. The method was validated in the two biological matrix according to guidelines set forth by COFRAC (Comité d'accréditation Français) self-declared current use of all other substances including tobacco products and nicotine replacement therapies, cannabis, and other substances using standardized TLFB (time line follow back) scales ) at the screening visit and every day from day 0 to 10 then at each study visit: 4 (1 per week) after discharge up to week 6 of the study in the subgroup of patients who declare themselves as current cannabis users at entry, urinary quantitative determination of cannabinoids by an extraction process and a chromatographic separation in LCMSHR (Liquid chromatography coupled to high resolution mass spectrometry) for quantification of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), 11-hydroxy Δ9-tetrahydrocannabinol (11-OH THC) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH) using deuterated molecules as internal standard. The method was validated in the two biological matrix according to guidelines set forth by COFRAC (Comité d'accréditation Français). This analyse will be centralized in the toxicology laboratory of Lariboisière hospital (Pr Laurence Labat). This analyse will be performed 6 times: 2 during the inpatient stay (D5 and D10) and 4 (1 per week) after discharge up to week 6 of the study. DESIGN Double Blind Randomized clinical trial with 3 arms : Patients will undergo one or several outpatient screening visits between D-30 and D-1 of inpatient entry. During this visit, the study design will be fully explained, inclusion and exclusion criteria checked. Patients will be included during this last visit. Three groups of 70 patients each will be randomized 1:1:1 at entry of a scheduled, usually lasting between 11 and 17 days, alcohol inpatient cessation (D0). They will all receive oxazepam plus an intervention: add-on placebo for 10 days during their inpatient stay add-on cannabidiol 450 mg per day for 10 days during their inpatient stay add-on cannabidiol 900 mg per day for 10 days during their inpatient stay. All groups will undergo the same prospective follow up after discharge with one visit per week to determine if alcohol abstinence is maintained, up to 1-month post-discharge (week 6 of the study). In case of a relapse, the amount of alcohol used will be recorded.

Official Title
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Cannabidiol as an add-on Treatment During Inpatient Alcohol Cessation in Patients With Severe Alcohol Use Disorder: A Phase II Trial

Conditions
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Severe Alcohol Use Disorder (DSM 5)

Intervention / Treatment
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* Drug: Placebo
* Drug: Half dose
* Drug: Full dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients hospitalized for a scheduled alcohol inpatient cessation Aged 18-75 years old Meeting DSM 5 criteria for severe AUD Willing to participate Signing a written informed consent Patients with current social insurance For childbearing age females: efficacious contraceptive method during treatment and up to seven days after treatment administration Exclusion Criteria: • Patients already scheduled for long term residential care after acute alcohol inpatient detoxification, not able to maintain the outpatient follow up Patients not willing to attend post-discharge visits whatever the reason Any unstable medical condition at entry, such as delirium, acute hepatic failure, hypokalaemia, liver cirrhosis whatever the stage, acute or chronic severe renal failure or any acute psychiatric condition Liver enzymes (ALT and/or AST) above 3 times the upper limit of normal and/or bilirubin above 2 times the upper limit of normal Current medication or need for medication with treatments metabolized by CYP 2C19 or CYP3A4 or UGT enzymes and having strong inhibitor/inducer properties (see list above), and/or current medication or need for medications containing valproate and derivates Any medical history of epileptic seizure Patients with current or past history of cardiac arrhythmias, myocardial infarction and stroke any history of suicidal attempt To facilitate efficacy data interpretation, patients currently receiving or wanting to receive another approved pharmacological treatment aimed at alcohol abstinence maintenance (acamprosate, baclofene, disulfiram, nalmefene, naltrexone). Other major current DSM 5 severe substance use disorder (like opiates, cocaine, amphetamines, sedatives, …..) except for tobacco and cannabis smoking. Pregnancy and breast feeding Known hypersensitivity to the active substance or to any of the excipients (including PEG) Patients under guardianship Patients in exclusion periods of other trials Reversely, cannabis use or cannabis use disorders will not be an exclusion criteria

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double Blind Randomized clinical trial with 3 arms :
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo<br>add-on placebo (Echo Pharmaceutical, BV) for 10 days during their inpatient stay | Drug: Placebo<br>* Placebo made by the same manufacturer to look like the active pills<br>* Other names: Placebo for 10 days during inpatient alcohol cessation;|
| Experimental: Half-dose<br>add-on cannabidiol (Echo Pharmaceutical, BV) 450 mg per day for 10 days during their inpatient stay | Drug: Half dose<br>* add-on cannabidiol (Echo Pharmaceutical, BV) 450 mg per day for 10 days during their inpatient stay<br>* Other names: Active half-dose for 10 days during inpatient alcohol cessation;|
| Experimental: Full dose<br>add-on cannabidiol (Echo Pharmaceutical, BV) 900 mg per day for 10 days during their inpatient stay | Drug: Full dose<br>* add-on cannabidiol (Echo Pharmaceutical, BV) 900 mg per day for 10 days during their inpatient stay<br>* Other names: Active fulldose of Cannabidiol for 10 days during inpatient alcohol cessation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| abstinence maintenance rate at week 6 of the study (1 month after discharge of the scheduled alcohol withdrawal inpatient stay). | Percentage of patients in each group with documented continuous abstinence at month 1 after discharge, week 6 of the study. | Week 6 | 
| Self-decalred abstinence verified by the investigator | Continuous abstinence will be defined by patients self-report of alcohol abstinence using standardized TLFB (time line follow back) scales TLFB at screening visit and daily from Day 0 to Day 10 and 4 (1 per week) after discharge up to week 6 of the study). Furthermore, this self-declaration will be confirmed by clinical examination at each study visits assessing acute alcohol intoxication signs and 6 ethyl glucuronide (EDTA) urinary assessments performed at each study visit (2 during the inpatient stay and 4 (1 per week) after discharge up to week 6 of the study). | Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| safety | symptoms check list (PRISE-M) of possible side effects every day from day 1 to 10, and then at each outpatient study visit (4 (1 per week) after discharge up to week 6 of the study). Thus any side effect related to treatment exposure as well as treatment cessation (such as anxiety rebound or withdrawal symptoms related to CBD or increase in cannabis use) could be documented | Day 1 to week 6 | 
| Alcohol reduction in case of relapse | In case of relapse: drinking days and drinks per day (self-declared using standardized TLFB time line follow back scale over the past week) at the screening visit and daily from Day 0 to Day 10 and 4 (1 per week) after discharge up to week 6 of the study) | Day 1 to week 6 | 
| Reduction of alcohol craving and withdrawal severity | alcohol withdrawal scales and craving scales (CIWA-R, , LIKERT craving scale and an adapt version of the OCDS) at the screening visit and every day from day 0 to 10 then at each study visit: 4 (1 per week) after discharge up to week 6 of the study | Day 1 to Week 6 | 
| Reduction in anxiety | state anxiety scale (STAI-6 the short form of the Spielberger inventory, composed of 6 Likert scales) at the screening visit and every day from day 0 to 10 then at each study visit: 4 (1 per week) after discharge up to week 6 of the study | Day 1 to Week 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CBD, Alcohol use disorder, Inpatient