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

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ClinicalTrials.gov Identifier: NCT03033823
Recruitment Status : Recruiting
First Posted : January 27, 2017
Last Update Posted : October 4, 2019
Sponsor:
Collaborator:
Ministry of Health, France
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Tracking Information
First Submitted Date  ICMJE January 3, 2017
First Posted Date  ICMJE January 27, 2017
Last Update Posted Date October 4, 2019
Actual Study Start Date  ICMJE November 16, 2017
Estimated Primary Completion Date November 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 24, 2017)
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 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 14, 2019)
  • Total benzodiazepine consumption compared between experimental and control groups throughout the duration of the study [ Time Frame: 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 ]
  • The rate of patients experiencing seizures and delirium tremens during the study compared between intervention and control groups [ Time Frame: 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • Patient Satisfaction Questionnaire-18 scores at the last follow-up point compared between experimental and control groups [ Time Frame: 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 ]
  • Rate of all adverse events occurred during the study and compare their incidence between intervention and control groups [ Time Frame: 15 days after randomization ]
Original Secondary Outcome Measures  ICMJE
 (submitted: January 24, 2017)
  • Total benzodiazepine consumption compared between experimental and control groups throughout the duration of the study [ Time Frame: 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 ]
  • The rate of patients experiencing seizures and delirium tremens during the study compared between intervention and control groups [ Time Frame: 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • Patient Satisfaction Questionnaire-18 scores at the last follow-up point compared between experimental and control groups [ Time Frame: 15 days after randomization ]
  • Total plasmatic 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 ]
  • Rate of all adverse events occurred during the study and compare their incidence between intervention and control groups [ Time Frame: 15 days after randomization ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE MAGnesium Adjunction in Alcohol Withdrawal Syndrome: a Multicenter Assessment (MAGMA)
Official Title  ICMJE Multicenter Randomized Placebo Controlled Trial Assessing the Efficacy of Oral Adjuvant Magnesium Supplementation in the Treatment of Alcohol Withdrawal Syndrome
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Alcohol Withdrawal Syndrome
Intervention  ICMJE
  • Drug: Magnesium
    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).
  • Drug: Placebo Oral Tablet
    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 Name: Placebo
Study Arms  ICMJE
  • 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).
    Intervention: Drug: Magnesium
  • 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.
    Intervention: Drug: Placebo Oral Tablet
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 24, 2017)
450
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 2019
Estimated Primary Completion Date November 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Guillaume Airagnes, M.D. 01.56.09.56.19 ext +33 guillaume.airagnes@aphp.fr
Contact: Frédéric Limosin, M.D., Ph.D. 01.58.00.44.21 ext +33 frederic.limosin@aphp.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03033823
Other Study ID Numbers  ICMJE P150939
2016-002072-26 ( EudraCT Number )
PHRC ( Other Grant/Funding Number: 15-613 )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE Ministry of Health, France
Investigators  ICMJE
Principal Investigator: Frédéric Limosin, M.D., Ph.D. Assistance Publique-Hôpitaux de Paris (AP-HP)
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP