Clinical trial NCT03033823: MAGnesium Adjunction in Alcohol Withdrawal Syndrome: a Multicenter Assessment (MAGMA)
Official title: Multicenter Randomized Placebo Controlled Trial Assessing the Efficacy of Oral Adjuvant Magnesium Supplementation in the Treatment of Alcohol Withdrawal Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Alcohol Withdrawal Syndrome
Keywords: Alcoholism
Delirium
Magnesium Deficiency
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Ministry of Health, France
First posted: 2017-01-27
Enrollment: 105
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study examine the efficacy of oral magnesium supplementation as an adjuvant therapy for decreasing intensity of alcohol withdrawal symptoms among inpatients requiring pharmacological treatment of their AWS. This double blind randomized multicenter clinical trial planned to treat half of participants as usal plus placebo and the other half as usual plus magnesium.

Detailed description: Alcohol withdrawal syndrome (AWS) is a frequent and potentially fatal outcome. It is crucial to treat AWS in order to reduce symptoms severity, to prevent severe complications and to increase patient motivation to maintain long-term alcohol abstinence. Clarify the relevance of oral magnesium supplementation as a routine adjuvant therapy of AWS can give rise to a major evolution of guidelines regarding management of alcohol use disorder and make AWS more comfortable for hundred thousand patients.

Magnesium acts as a competitor of glutamate on NMDA receptor binding site, limiting glutamate toxicity leading to AWS. Previous findings suggested a correlation between AWS intensity and hypomagnesaemia degree, and an increased risk of severe AWS (i.e. delirium tremens and seizure) when there is deep depletion. In addition to magnesium role as a glutamatergic modulator via an NMDA-receptor antagonism activity, magnesium may also modulate GABAergic neurotransmission and affect numerous transduction pathways, including proteinkinase C, possibly influencing the access of corticosteroids to the brain.

Moreover, magnesium has been found to be a cofactor required for thiamine-dependent enzymes whereas thiamine supplementation is crucial to prevent from Wernicke's encephalopathy in the treatment of AWS. Finally, magnesium supplementation could help to reduce benzodiazepines use.

The primary endpoint is the between-group absolute difference of the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar) score change from baseline, 3 days after randomization.

The secondary endpoints are:

a Total benzodiazepine consumption compared between experimental and control groups throughout the duration of the study (i.e. 15 days); b Time required to obtain a total score of 0 at the CIWA-Ar compared between experimental and control groups; c Rate of patients experiencing seizures and delirium tremens during the study compared between intervention and control groups; d Stratify results of the Primary endpoint following score at the Charlson Comorbidity Index; e Stratify results of the Primary endpoint by age; f Number of participants who left the hospital against medical advice during the study compared between experimental and control groups; g Number of participants who made an appointment in an addiction unit during the study (i.e. before the last follow-up point, 15 days after baseline), compared between experimental and control groups after stratification following AUD duration and number of previous addiction healthcare; h Patient Satisfaction Questionnaire-18 (PSQ-18) scores at the last follow-up point (i.e. days after baseline) compared between experimental and control groups; i Total plasmatic or serum magnesium concentration changes between baseline, 3 days after baseline, and 7 days after baseline; j Rate of all adverse events occurred during the study incidence compared between experimental and control groups;

Practical procedure:

Patients recruited are inpatients, hospitalized whatever the main reason for hospitalization (i.e. alcohol withdrawal syndrome or other reason). Inclusion visit starts with signature of informed consent, then confirms the eligibility and finally, ends with randomization and administration of the first dose of treatment. Patients are followed 15 days after baseline. Total plasmatic or serum magnesium concentration is dosed at baseline, 3 days and 7 days. In addition to CIWA-Ar and AUDIT, the following assessments are performed at baseline: Charlson comorbidity index, DIGS, SCL-90, MINI. We will use tablets of 465.4 mg of magnesium lactate dehydrate (Magnespasmyl©), which corresponds to 47.4mg of magnesium (i.e. 1.9mmol of magnesium per tablet). These tablets will be prescribed as follows: 3 tablets three times per day. In case of diarrhea, nearly half-dosage will be used until the end of the follow-up (i.e. 189.6mg per day, 3 times a day as follows: 1 tablet, 2 tablets, 1 tablet). Patients will be informed that treatment is to be taken during meals and to avoid sodas during the study.

Eligibility criteria: Inclusion Criteria:

* Adult inpatients, men and women (i.e. age\>18 years and \<75 years) ;
* Current AWS according to DSM-5 criteria;
* Score at the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar) \>8;
* Written informed consent to participate in the study;
* Affiliation to the French Social Security Health Care plan.

Exclusion Criteria:

* Age less than 18 or greater than 75;
* Hemodynamic failure;
* Arythmia;
* Lack of fulfilling AWS criteria according to DSM-5;
* Score at the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar) \<=8;
* Benzodiazepine misuse according to the opinion of the investigator;
* Substance use disorder according to the opinion of the investigator, regarding licit and illicit substances, except for tobacco;
* Pregnancy or breast-feeding;
* Unable to take oral medications;
* Creatinine clearance \< 45mL/min less than 6 months old. If there is no dosage in the last 6 months, creatinine clearance must be \<30mL/min at inclusion (creatinine clearance computed according to the Cockcroft-Gault Equation);
* Cognitive disorders already known at inclusion that impair the informed consent, including dementia (except for acute withdrawal delirium), according to the opinion of the investigator;
* Psychiatric disorder requiring hospitalization or specific cares in emergency (e.g. suicidal crisis, acute psychotic episode);
* Magnesium supplementation (regardless the type of delivery) within 3 months prior to inclusion;
* Actual quinidine intake;
* No written informed consent to participate in the study;
* Patient under tutorship or curatorship;
* Hypersensitivity to Magnespasmyl® or to any of its excipients (including sucrose) or to lactose (placebo excipient).

Primary outcomes:
measure: Between-group absolute difference of the CIWA-Ar score (revised clinical institute withdrawal assessment for alcohol scale) change from baseline
timeFrame: 3 days after randomization
Secondary outcomes:
measure: Total benzodiazepine consumption compared between experimental and control groups throughout the duration of the study
timeFrame: 15 days after randomization
measure: The delay compared between experimental and control groups until having a total score of 0 at the CIWA-Ar
timeFrame: 15 days after randomization
measure: The rate of patients experiencing seizures and delirium tremens during the study compared between intervention and control groups
timeFrame: 15 days after randomization
measure: Between-group absolute difference of the CIWA-Ar score change from baseline, considering two subgroups: score at the Charlson Comorbidity Index (CCI) min-score at the CCI median versus score score at the CCI median-score at the CCI min
timeFrame: 3 days after randomization
measure: Between-group absolute difference of the CIWA-Ar score (revised clinical institute withdrawal assessment for alcohol scale) change from baseline considering two subgroups: 18-59 years versus 60-75 years
timeFrame: 3 days after randomization
measure: The number of participants who left the hospital against medical advice during the study compared between intervention and control groups
timeFrame: 15 days after randomization
measure: The number of participants who made an appointment in an addiction unit during the study compared between intervention and control groups after stratification following alcohol use disorder (AUD) duration and number of previous addiction healthcare
timeFrame: 15 days after randomization
measure: Patient Satisfaction Questionnaire-18 scores at the last follow-up point compared between experimental and control groups
timeFrame: 15 days after randomization
measure: Total plasmatic or serum magnesium concentration changes between baseline,3 days after baseline, and 7 days after baseline, compared between intervention and control groups
timeFrame: 3 days and 7 days after randomization
measure: Rate of all adverse events occurred during the study and compare their incidence between intervention and control groups
timeFrame: 15 days after randomization
Other outcomes:
Locations:
city: Colombes
country: France
facility: Hôpital Louis Mourier, AP-HP
state: Ile-de-France
city: Epinay sur Seine
country: France
facility: Clinique des Platanes
state: Ile-de-France
city: Issy-les-Moulineaux
country: France
facility: Hôpital Corentin Celton, AP-HP
state: Ile-de-France
city: Le Mesnil Saint Denis
country: France
facility: Institut MGEN de la Verriere
state: Ile-de-France
city: Le Mesnil saint Denis
country: France
facility: Institut MGEN la Verriere-service SSR addictologie
state: Ile-de-France
city: Paris
country: France
facility: Clinique des maladies mentales et de l'encéphale
state: Ile-de-France
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou-Service de chirugie orthopédique, AP-HP
state: Ile-de-France
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou-Service de médecine interne, AP-HP
state: Ile-de-France
city: Paris
country: France
facility: Hôpital européen Georges-Pompidou-Service hépato-gastroentérologie
state: Ile-de-France
city: Sevres
country: France
facility: Centre Hospitalier des quatre villes
state: Ile-De-France
city: Limeil-Brévannes
country: France
facility: Hôpital Emile ROUX
Study officials:
affiliation: Assistance Publique-Hôpitaux de Paris (AP-HP)
name: Frédéric Limosin, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: