Baclofen for Improving Benzodiazepine Titration in Benzodiazepine Dependence

Phase 3RecruitingNCT05935553

Hospices Civils de Lyon93 enrolled

Overview

Benzodiazepines and related molecules are among the most prescribed psychotropic treatments in France and Europe. 13.4% of the French population had at least one reimbursement of benzodiazepines in 2015, which places France second in Europe. However, the chronic use of benzodiazepines is a source of numerous complications, particularly addictive. To date, there is no authorized pharmacological treatment for benzodiazepine withdrawal. Baclofen is a gamma-aminobutyric acid (GABA)-B agonist, a pharmacological receptor that regulates GABA-A, the target of benzodiazepines. The pharmacological mechanisms of baclofen are therefore related to those of benzodiazepines. Empirical use outside of the MA has shown that baclofen can facilitate the reduction of benzodiazepines in cases of severe addiction, but this pharmaceutical interest remains to be demonstrated in a comparative study. The main objective of the project is to evaluate the efficacy of baclofen, compared to placebo, in reducing benzodiazepine doses in patients with benzodiazepine use disorder (BUD).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Benzodiazepine Dependence

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Patients aged ≥ 18 years to ≤ 65 years * For women of childbearing potential : * negative pregnancy test at inclusion * and use of effective contraception which will be continued throughout the trial period * and agrees to carry out pregnancy tests throughout the trial period. * BUD of any severity defined according to Diagnostic and Statistical Manual of Mental Disorders (DSM) 5 criteria * Average daily benzodiazepine dosage between 30 mg and 200 mg-diazepam (according to Ashton equivalence table) over the 28 days prior to inclusion. Benzodiazepine equivalents (zolpidem, zopiclone and eszopiclone) will be counted as part of the total equivalent daily dose of diazepam and will also be included in the tapering procedure. * Continued use of benzodiazepines for more than 12 weeks * At least one history of BUD treatment failure. A treatment failure is defined as a failure to withdraw from the full dose (i.e., discontinuation of benzodiazepine and related prescriptions) according to a previously established tapering schedule, by a general practitioner or specialist * Patient affiliated to a social security system. * Patients with or without guardianship * Patient capable of giving free, informed and written consent. Exclusion Criteria: * Cirrhosis of the liver * Patients with significant medical conditions such as cancer, HIV, epilepsy, chronic respiratory failure, renal failure, etc. * Non-compatible health conditions (at the discretion of the investigator) * The following psychiatric conditions as defined by DSM-5 criteria: schizophrenic disorder, persistent delusional disorder, schizophreniform disorder, schizoaffective disorder, bipolar disorder, autism spectrum disorder identified using the Mini International Neuropsychiatric Interview version 7.0.2 (MINI 7.0.2) * Suicidal state identified using MINI 7.0.2 * Dependence on substances or drugs other than benzodiazepines and nicotine (dependence will be identified through the use of MINI 7.0.2) * History of baclofen use for all indications * Unauthorized combination therapies will be: pregabalin, topiramate, ketamine, sodium oxybate, gabapentin, valproic acid, sodium valproate, melatonin, buspirone, hydroxyzine, propranolol, bisoprolol, etifoxin, carbamazepine, clonidine, paroxetine, all neuroleptic/antipsychotic class therapies, and tricyclic antidepressants * Pregnant or nursing women * Hypersensitivity to baclofen or microcrystalline cellulose. * Participants under guardianship * Patients who need to drive and/or use machines during the 1-week dose escalation phase

Outcomes

Primary Outcomes

Difference in total benzodiazepine consumption, in mg-diazepam

This difference will be compared between the two groups (winning baclofen group and placebo group). Total benzodiazepine consumption will be measured using the Benzodiazepine Timeline Follow-Back (B-TLFB). A mean value (in mg/d) for the 28 days of consumption will be calculated for each patient (between the 28 days prior to inclusion in the clinical trial and the last 28 days of the clinical trial).

Time frame: between the 28 days before inclusion in the clinical trial and the last 28 days of the clinical trial

Secondary Outcomes

Frequency of serious adverse events of special interest

The frequency of serious adverse events of particular interest will be collected from inclusion to the end of the study for each patient.

Time frame: through study completion, an average of 4 and a half months

Frequency of non-serious adverse events of special interest

The frequency of non-serious adverse events of particular interest will be collected from inclusion to the end of the study for each patient.

Time frame: through study completion, an average of 4 and a half months

frequency of all-cause study discontinuations

frequency of all-cause study discontinuations will be collected from inclusion to the end of the study for each patient.

Time frame: through study completion, an average of 4 and a half months

Frequency of benzodiazepine discontinuation at the last visit of the treatment period by urine test

Toxicology will be measured by a urine test during the last visit of the treatment period.

Time frame: at study completion, an average of 4 and a half months

Frequency of benzodiazepine discontinuation at the last visit of the treatment period by B-TLFB questionnaire

Frequency of benzodiazepine discontinuation at the last visit of the treatment period will collected by B-TLFB questionnaire. The B-TLFB involves asking patients to retrospectively estimate their benzodiazepine consumption.

Time frame: at study completion, an average of 4 and a half months

Frequency of benzodiazepine discontinuation at the last visit of the treatment period by the Clinical Institute Withdrawal Assessment of Benzodiazepine (CIWA-B) questionnaire

The severity score for benzodiazepine withdrawal will be assessed at visit 1 to visit 6 by the Clinical Institute Withdrawal Assessment of Benzodiazepine (CIWA-B).The B-TLFB involves asking patients to retrospectively estimate their benzodiazepine consumption. The CIWA-B comprises client-reported symptoms and clinical observations. Questions 1-11 and 13-17 are client-reported symptoms, with each scored on five-point scales from 0 = not at all to 4 = very much so. Question 12 is also a client-reported item, but the 5 scale is reversed, i.e., 0 = Very much so to 4 = Not at all. Questions 18-20 are clinical observations, with all three scored on five-point scales (i.e. 0, 1, 2, 3 or 4). A total score is obtained by summing questions 1-20: The minimum total score possible is 0, and the maximum total score possible is 80. 1-20 Mild withdrawal 21-40 Moderate withdrawal 41-60 Severe withdrawal 61-80 Very severe withdrawal