Effect of AEF0117 on Treatment-seeking Patients With Cannabis Use Disorder (CUD)

Cannabis use is increasing and will only further escalate with legalization of recreational and medical cannabis use in western countries , with a prevalence greater than 30 % in the US and most European countries for individuals between 16 and 24 years of age. Approximately 9 % of those who use cannabis will become addicted. The number goes up to about 1 in 6 among those who start using cannabis as teenagers and to 25 to 50 % among those who smoke cannabis daily. The consequences of cannabis abuse in the most prone population (14-25 years of age) are extremely serious, and may include addiction, altered brain development, poorer educational outcomes, cognitive impairment, lower income, greater welfare dependence, unemployment and lower relationship and life satisfaction. There are no available pharmacological treatments of cannabis use disorder (CUD). Thus, the development of safe and effective medications for the treatment of CUD is an urgent public health priority. The preclinical efficacy and available ADMET (Administration, Distribution, Metabolism, Elimination and Toxicology) in animal and human data suggest that AEF0117, an investigational new study drug, could constitute a very efficacious and safe treatment for cannabis abuse disorders. The purpose of this research is to study how AEF0117 influences the subjective effects of cannabis in subjects with CUD. AEF0117 acts in the same parts of the brain as THC (tetrahydrocannabinol), the active ingredient of marijuana, and may temporarily alter some of cannabis's effects. The safety and tolerability of AE0117 has been demonstrated in the clinical studies conducted to date. This study will provide additional data on the efficacy of AEF0117 on treatment-seeking subjects with moderate to severe CUD. This will be a phase 2b, randomized, double-blind, placebo-controlled, 4-arm, parallel-group, prospective, multicenter study. The overall purpose of this study is to assess the efficacy and safety of AEF0117 in subjects with moderate to severe CUD who are treatment-seeking. The overall purpose of this study is to assess the efficacy and safety of AEF0117 in subjects with moderate to severe CUD who are treatment-seeking. Up to 330 eligible male or female subjects will be randomized into 1 of 4 treatment groups. Due to the difference in prevalence of CUD between males and females, the number of females enrolled is anticipated to be less than 1/3 of all subjects. Moreover, the number of female subjects to be enrolled will be limited via stratification ensuring that a maximum 80 females will be assigned to active treatment (i.e., to 1 of the AEF0117 treatment groups), considering the development stage of the compound. Subjects will be randomized to 1 of 4 treatment groups: * AEF0117 1.0 mg once daily (QD) (90 subjects) * AEF0117 0.3 mg QD (90 subjects) * AEF0117 0.1 mg QD (60 subjects) * Placebo QD (90 subjects) The primary objective of this study is to demonstrate that AEF0117 induces a greater proportion of RESPONDERS (i.e., subjects with a RESPONSE of ≤1 day of cannabis use per week) compared to placebo in treatment-seeking subjects with moderate to severe CUD, according to DSM-5 criteria. The secondary objectives are to investigate the proportion of subjects that reach various levels of reduction and how this influences their quality of life, and to evaluate the safety and tolerability of AEF0117. * Assess if AEF0117 increases the proportion of subjects that reach complete abstinence (0 cannabis use). * Assess if AEF0117 increases the proportion of subjects that have a modest level of cannabis use (≤2 days per week). * Assess if AEF0117 increases the proportion of subjects that report no CUD symptoms according to DSM-5 except for craving (modified early remission, which is defined by the same criteria of the DSM-5 but without the required minimal time duration of the remission). * Assess if AEF0117 decreases the percentage of days of cannabis use. * Assess if AEF0117 improves the quality of life as measured by the Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) adult profile. * Assess if AEF0117 introduce a change in pattern of cannabis use over the day. * Assess the safety and tolerability of AEF0117. The exploratory objectives of this study are to further evaluate the effect of AEF0117 on pattern of cannabis use and change in various signs and symptoms, and in addition to assess effects during the grace period and the entire treatment period. The study consists of a screening period, a double-blind treatment period which includes a grace period and a treatment ascertainment period, and a follow-up period. The study will be conducted on an outpatient basis at the sites with a total of 27 visits per subject after screening for eligibility. During the 12-week treatment period, 25 visits will be performed: 1 weekly visit will include most of the scheduled assessments (13 full visits), while the second weekly visit will only include few assessments (12 short visits).Under certain circumstances, a short visit may be converted to a remote visit if it does not pose a risk to the safety of the subject as judged by the investigator. During the 4-week follow-up period, 2 visits approximately 14 days apart will take place. The double-blind randomized treatment period will consist of 2 periods: a 4-week grace period and an 8-week treatment ascertainment period. During both periods, subjects will attend standardized medical management sessions once a week with trained professionals (i.e., 12 visits in total). During the grace period (Day 1 to Day 28), cannabis use will not be a criterion for characterization of non-responding subjects. This period will allow AEF0117 to reach plasma steady state and allow for behavioral changes. During the treatment ascertainment period (Day 29 to Day 84), any cannabis use will be taken into consideration to assign subjects as responders and non-responders. All study visits will be conducted on an outpatient basis at the sites. Screening visit(s), weekly full visits during the grace period and treatment ascertainment period (13 visits) and visits every second week during follow up (2 visits) include extended assessments. In addition, 1 short visit per week is scheduled during the grace period and treatment ascertainment period (12 visits), including a few assessments (the second of the twice weekly visits). Efficacy will be assessed using different observer-rated and self-reported scales. Self-reported cannabis use will be monitored daily, prospectively by an Ecological Momentary Assessment (EMA) using a smartphone-based application and retrospectively by using the TLFB procedure. The documentation of self-reported cannabis use will be based primarily on the EMA data and, in the case of missing data, on the TLFB data. In the case of a discrepancy, the more conservative data will be used (i.e., presence of an episode of use). Adverse events will be monitored by research staff and medical observations and spontaneous reporting throughout the study. The grading system of adverse events used in this study will be the grading system proposed by Sibille M., et. al. Specifications on the grading system for clinical observations and ECG parameters will be based on the publication by Sibille M, Patat A, et al. Vital signs and laboratory parameters will be based on the FDA vaccine guidance (The Biologics Blood Vaccines Guidance Compliance, FDA).