Baclofen for Improving Benzodiazepine Titration in Benzodiazepine Dependence

Обзор

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).

Вмешательства

• Препарат Baclofen 30 mg
  * baclofen 10 mg capsule (for the 30 mg-baclofen 30 mg arm) * Dosage: 3 capsules of baclofen 10 mg per day * route of administration: Oral * duration of treatment: Total duration of treatment is 13 weeks including 1 week of dose escalation, 11 weeks of maintenance at full dose, and 1 week of dose de-escalation
• Препарат Baclofen 60 mg
  * baclofen 20 mg capsule (for the 60 mg baclofen arm) * Dosage: 3 capsules of baclofen 20 mg per day * route of administration: Oral * duration of treatment: Total duration of treatment is 13 weeks including 1 week of dose escalation, 11 weeks of maintenance at full dose, and 1 week of dose de-escalation
• Препарат Placebo
  * placebo capsule (for the placebo arm) * Dosage:3 capsules of placebo per day * route of administration: Oral * duration of treatment: Total duration of treatment is 13 weeks including 1 week of dose escalation, 11 weeks of maintenance at full dose, and 1 week of dose de-escalation

Первичные конечные точки

• Difference in total benzodiazepine consumption, in mg-diazepam [Срок оценки: between the 28 days before inclusion in the clinical trial and the last 28 days of the clinical trial]

Вторичные конечные точки (11)

• Frequency of serious adverse events of special interest [Срок оценки: through study completion, an average of 4 and a half months]
• Frequency of non-serious adverse events of special interest [Срок оценки: through study completion, an average of 4 and a half months]
• frequency of all-cause study discontinuations [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: up to visit 6, an average of 3 and a half months]
• Craving score assessed by the Visual Analog Scale (VAS) [Срок оценки: up to visit 6, an average of 3 and a half months]
• Anxiety symptoms assessed by the State Trait Inventory Anxiety (STAI-Y) [Срок оценки: up to visit 6, an average of 3 and a half months]
• Depression score assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) [Срок оценки: up to visit 6, an average of 3 and a half months]
• Subjective sleep quality assessed by the Pittsburgh Sleep Quality Index (PSQI) [Срок оценки: up to visit 6, an average of 3 and a half months]
• Quality of life (SF-12 v2) [Срок оценки: up to visit 6, an average of 3 and a half months]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Двойное слепое

Основная цель

Лечение

Центры проведения

Франция · 2 центра

• Centre Hospitalier le Vinatier — Bron
• Hôpital Edouard Herriot — Lyon

Идентификаторы

NCT: NCT05935553 · 69HCL21_1318 · 2022-502307-30-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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