1. CLINICAL EFFICACY STUDY OF BACLOFEN IN REDUCING ALCOHOL CONSUMPTION IN HIGH RISK DRINKERS Study title: Alcohol Treatment : A Pragmatic Randomized, Double-blind One year therapeutic trial in Ambulatory Care comparing Baclofen Versus Placebo. (ClinicalTrials.gov Identifier: NCT01604330) Coordinating investigator: P.JAURY * Scientific Committee: J.R. Legall, A. Benyamina, R. de Beaurepaire, H. Falcoff. Independent Data Safety Monitoring Board: N. Simon, J.B. Trabut, L. Moachon. Chief Scientist: C. Le Jeunne. Methodologists: J. Coste, L. Rigal. Clinical Research Unit Paris Centre: J.M. Treluyer, S. Poignant, A. Bruneau. *E-mail address: philippe.jaury@parisdescartes.fr Introduction Alcoholism is a serious public health issue with unmet medical needs. In France, a person dies every 12 minutes because of alcoholism. Baclofen, a gamma-aminobutyric acid 'B-receptor' agonist, has long been used to treat spasticity from neurological diseases, at a dose of 30-90 mg/day. It appears today to be a promising but controversial candidate for treating alcoholic patients (Enserick, 2011) by reducing or even suppressing their craving to drink. A few case reports (Ameisen, 2005; Bucknam, 2007; Dore et al., 2011) and two retrospective study (Rigal et al, 2012, de Beaurepaire 2012) suggest that some patients might respond favorably to baclofen at higher doses than 90 mg/day. Larger randomized trials are necessary to define the role of baclofen in alcohol dependence. The French regulatory authorities have implemented in March 2014 a “Temporary Recommendation Use” for baclofen in alcohol dependence. Objectives Primary : To show the effectiveness of one year treatment of baclofen compared to placebo on the reduction of alcohol consumption. The primary endpoint is the percentage of patients in each group with a low risk alcohol consumption or abstinent, according to the WHO standards (12 months after treatment initiation). Secondary :  To describe the distribution of the effective dosage of baclofen (Published studies indicate that the average dose may be around 140 mg per day unrelated to the weight of the patient. Animal studies show an optimal dose of 3 mg/kg.)  To assess the tolerance of baclofen and note all adverse events  To try to evaluate the causal relationship between adverse events and baclofen, alcohol withdrawal or alcohol-baclofen potentiation (compared to placebo group)  To describe characteristics of responders to baclofen: anxiety/depression HAD scale, craving scale (OCDS), DSM - IV and ADS criteria for dependence  To assess quality of life during treatment by using SF36 scale at the beginning and at the end of the study  To study the change in biological parameters compared to patient declarations regarding the response to treatment. Biological sampling will be performed at the beginning, at 6 month and at the end of the trial. Methodology Multicentric, comparative, randomized, two parallel groups, double blind study compared to placebo. Pragmatic trial. Number of patients Hypothesis: low risk alcohol consumption: 45 % in the baclofen group and 20 % in the placebo group. Inclusion criteria  Adult patient (18-65) with an alcohol problem (high risk alcohol consumption during the past three months: at least two times per month) according to the WHO standards.  Volunteer to participate in the trial and having given his written informed consent  No treatment for maintenance of abstinence (acamprosate, naltrexone) or prevention of relapse (disulfiram) for at least 15 days before the beginning of the trial  Patient informed about the possibility of drowsiness due to the treatment, the associated risks to drive vehicles (motorized or not) or use machines (including domestic use or recreation) and the execution of tasks requiring attention and precision Therapeutic schedule Drug: Baclofen Baclofen will be administered orally for a maximum of 52 consecutive weeks. For the first 3 days, patients will receive baclofen in a dose of 5 milligrams three times a day; then the dose of baclofen will be increased to a maximum of 300 milligrams a day. In case of intolerance, dosage can be decreased. Drug: Placebo Sugar pill will be administered orally for a maximum of 52 consecutive weeks. For the first 3 days, patients will receive sugar pill in a dose of 5 milligrams three times a day; then the dose of sugar pill will be increased to a maximum of 300 milligrams a day. In case of intolerance, dosage can be decreased. Conclusion 321patients have been included and randomized in one year (June 2012- June 2013). The end of study is planned in June 2014, and results are expected in November 2014. This trial is sponsored by Assistance Publique - Hôpitaux de Paris (Chief Project: Y. Vacher). BACLOVILLE