MAGnesium Adjunction in Alcohol Withdrawal Syndrome: a Multicenter Assessment (MAGMA) (MAGMA)

December 20, 2021 updated by: Assistance Publique - Hôpitaux de Paris

Multicenter Randomized Placebo Controlled Trial Assessing the Efficacy of Oral Adjuvant Magnesium Supplementation in the Treatment of Alcohol Withdrawal Syndrome

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.

Study Overview

Status

Completed

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.

Study Type

Interventional

Enrollment (Actual)

105

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Limeil-Brévannes, France
        • Hôpital Emile Roux
    • Ile-De-France
      • Sevres, Ile-De-France, France, 92310
        • Centre Hospitalier des quatre villes
    • Ile-de-France
      • Colombes, Ile-de-France, France, 92700
        • Hôpital Louis Mourier, AP-HP
      • Epinay sur Seine, Ile-de-France, France, 93800
        • Clinique des Platanes
      • Issy-les-Moulineaux, Ile-de-France, France, 92130
        • Hôpital Corentin Celton, AP-HP
      • Le Mesnil Saint Denis, Ile-de-France, France, 78322
        • Institut MGEN de la Verriere
      • Le Mesnil saint Denis, Ile-de-France, France, 78322
        • Institut MGEN la Verriere-service SSR addictologie
      • Paris, Ile-de-France, France, 75014
        • Clinique des maladies mentales et de l'encéphale
      • Paris, Ile-de-France, France, 75015
        • Hôpital Européen Georges Pompidou-Service de chirugie orthopédique, AP-HP
      • Paris, Ile-de-France, France, 75015
        • Hôpital Européen Georges Pompidou-Service de médecine interne, AP-HP
      • Paris, Ile-de-France, France, 75015
        • Hôpital européen Georges-Pompidou-Service hépato-gastroentérologie

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Intervention
Usual care (i.e. without any restriction of drug therapy) plus oral tablet magnesium supplementation: 426.6mg of magnesium per day three times daily (i.e. 142.2 mg for each shot) throughout the study (i.e. fifteen days). In case of diarrhea, nearly half-dosage will be used (i.e. 189.6mg).
Usual care (i.e. without any restriction of drug therapy) plus oral tablet magnesium supplementation: 426.6mg of magnesium per day three times daily (i.e. 142.2 mg for each shot) throughout the study (i.e. fifteen days). In case of diarrhea, nearly half-dosage will be used (i.e. 189.6mg).
Placebo Comparator: Control
Usual care (i.e. without any restriction of drug therapy) plus oral placebo, totally similar to the verum, three times daily throughout the study (i.e. fifteen days). In case of diarrhea, nearly half-dosage will be used.
Usual care (i.e. without any restriction of drug therapy) plus oral placebo, totally similar to the verum, three times daily throughout the study (i.e. fifteen days). In case of diarrhea, nearly half-dosage will be used.
Other Names:
  • Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Between-group absolute difference of the CIWA-Ar score (revised clinical institute withdrawal assessment for alcohol scale) change from baseline
Time Frame: 3 days after randomization
3 days after randomization

Secondary Outcome Measures

Outcome Measure
Time Frame
Total benzodiazepine consumption compared between experimental and control groups throughout the duration of the study
Time Frame: 15 days after randomization
15 days after randomization
The delay compared between experimental and control groups until having a total score of 0 at the CIWA-Ar
Time Frame: 15 days after randomization
15 days after randomization
The rate of patients experiencing seizures and delirium tremens during the study compared between intervention and control groups
Time Frame: 15 days after randomization
15 days after randomization
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
Time Frame: 3 days after randomization
3 days after randomization
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
Time Frame: 3 days after randomization
3 days after randomization
The number of participants who left the hospital against medical advice during the study compared between intervention and control groups
Time Frame: 15 days after randomization
15 days after randomization
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
Time Frame: 15 days after randomization
15 days after randomization
Patient Satisfaction Questionnaire-18 scores at the last follow-up point compared between experimental and control groups
Time Frame: 15 days after randomization
15 days after randomization
Total plasmatic or serum magnesium concentration changes between baseline,3 days after baseline, and 7 days after baseline, compared between intervention and control groups
Time Frame: 3 days and 7 days after randomization
3 days and 7 days after randomization
Rate of all adverse events occurred during the study and compare their incidence between intervention and control groups
Time Frame: 15 days after randomization
15 days after randomization

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Frédéric Limosin, M.D., Ph.D., Assistance Publique-Hôpitaux de Paris (AP-HP)

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 16, 2017

Primary Completion (Actual)

October 23, 2020

Study Completion (Actual)

October 23, 2020

Study Registration Dates

First Submitted

January 3, 2017

First Submitted That Met QC Criteria

January 24, 2017

First Posted (Estimate)

January 27, 2017

Study Record Updates

Last Update Posted (Actual)

December 21, 2021

Last Update Submitted That Met QC Criteria

December 20, 2021

Last Verified

December 1, 2021

More Information

Terms related to this study

Other Study ID Numbers

  • P150939
  • PHRC (2001/1939)
  • 2016-002072-26 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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